T cells expressing allograft inflammatory factor 1 display increased chemotaxis and induce a profibrotic phenotype in normal fibroblasts in vitro

Abstract

Objective. Allograft inflammatory factor 1 (AIF-1) was first identified in rat cardiac allografts undergoing chronic rejection. The vasculopathy of chronic allograft rejection is strikingly similar to that seen in patients with systemic sclerosis (SSc). We previously demonstrated AIF-1 expression in inflammatory cells infiltrating skin and lungs from SSc patients, but its role in SSc pathogenesis is unknown. The present study was undertaken to investigate the effects of AIF-1 on T cell migration and production of cytokines capable of modulating normal dermal fibroblast functions.Methods. Stably transfected Jurkat T cells expressing 2 AIF-1 splicing variants were prepared, and their migration toward fibroblast monolayers assayed in Transwell cultures. Cytokine production was assessed by real-time polymerase chain reaction (PCR) and multiplex enzyme-linked immunosorbent assay. Fibroblast gene expression was quantified by real-time PCR, and collagen production by Western blot analysis of culture media.Results. AIF-1 significantly increased Jurkat T cell migration toward fibroblast monolayers. Expression of AIF-1 isoform 2 in Jurkat T cells up-regulated their production of interleukin-4 (IL-4) and IL-17. Conditioned media from AIF-1-expressing clones stimulated synthesis of types I and III collagen and expression of IL-6, transforming growth factor ␤, endothelin receptor, and ␣-smooth muscle actin by normal dermal fibroblasts.Conclusion. These results suggest that AIF-1 may participate in the early pathogenesis of SSc by promoting tissue T cell infiltration and production of cytokines capable of inducing the expression of a fibrotic phenotype in normal fibroblasts.

Loss of Allograft Inflammatory Factor-1 Ameliorates Experimental Autoimmune Encephalomyelitis by Limiting Encephalitogenic CD4 T-Cell Expansion

“…Expression of Aif-1 increases above basal levels in these cell types (16)(17)(18) in neuro-inflammatory disease models (19). Conceivably, increased expression of Aif-1 during EAE pathogenesis (20,21) could promote T cell, macrophage and/or microglial proinflammatory functions and overall disease activity.…”

“…Largely similar gene products arising from the same locus have been named Iba1, microglial response factor-1 (MRF1) and daintain; Iba1 in particular is a well-known histologic marker of microglia and of their activation in pathological CNS conditions. Aif-1 is differentially expressed in various mouse and human tissues (14,15) and in multiple leukocyte types including macrophages and T cells at basal levels (16)(17)(18). In inflammatory disease models, upregulated Aif-1 expression has been reported in microglia, macrophages, T cells, synoviocytes, pancreatic β-cells and adipocytes under various pathological conditions representing encephalomyelitis, uveitis, neuritis, arteriopathies, arthritis and diabetes, respectively (19).…”

Effects of Daintain/AIF-1 on β Cell Dysfunction in INS-1 Cells

“…Daintain/AIF-1 is regarded as a novel inflammatory factor that plays important roles in allograft rejection, vasculopathy, and autoimmune diseases such as experimental autoimmune neuritis, encephalomyelitis, and uveitis models, 7,8) rheumatoid arthritis, 9) and systemic sclerosis. 10,11) Type-1 (insulin-dependent) diabetes (T1D) is characterized by a progressive autoimmune-mediated insulitis culminating in the death of pancreatic cells. The cell secretory dysfunction and apoptosis in the course of insulitis are perhaps caused by direct contact with activated macrophages and T-cells, and/or exposure to inflammatory mediators secreted by these cells, including cytokines (such as IL-1, TNF-, and IFN-) and NO.…”

Allograft inflammatory factor-1 is overexpressed and induces fibroblast chemotaxis in the skin of sclerodermatous GVHD in a murine model

“…These factors are intricately intertwined and induce multiple clinical manifestations, but have not been elucidated in detail yet. In cells and tissues of various diseases including SSc, AIF-1 is expressed in T cells [14,15], macrophages, and endothelial cells [16,17] and may promote the expression of adhesion molecules that mediate specific homing into affected tissues [7]. Another recent study in vitro indicated that AIF-1 enhances the activation of T cells, which increase chemotaxis and induces a profibrotic phenotype [15,14], but the T cells are forcedly transfected with the vector expressing AIF-1.…”